Group B coxsackieviruses (CVB) are a leading cause of infectious myocarditis. Although the replication of enteroviruses is generally well understood, our understanding of CVB pathogenesis is incomplete, and is largely based on inferences from tissue culture studies, and the use of murine models. Tissue specific determinants of viral replication have not been extensively evaluated, but the existence of replication competent but non-myocarditic CVB variants indicates that there are likely to be factors that restrict or augment replication in cardiac myocytes. This difference in the pathogenic potential of myocarditic and non-myocarditic variants of CVB has been mapped to viral internal ribosome entry site (IRES), found in the 5'untranslated region of the coxsackievirus genome. We speculate that interactions between cellular proteins and the IRES determine the myocarditic potential of coxsackieviruses. If this hypothesis is correct, understanding the nature of these interactions may suggest novel therapeutic strategies to treat acute myocarditis, or to interfere with the evolution of dilated cardiomyopathy. Consequently, we propose experimental approaches to identify factors found in primary cardiac myocytes that interact with the IRES of CVB, and to clarify their functional significance in CVB replication. Project Narrative: We propose experiments to comprehensively identify proteins within heart muscle cells (cardiac myocytes) that allow coxsackieviruses to infect and injure the heart. These experiments will aid our understanding of viral myocarditis and may lead to new therapies for this life-threatening illness.